Type 2 Hypersensitivity (Antibody-Mediated Cytotoxic Hypersensitivity)

Overview

Mechanism

1. Complement-Mediated Cytotoxicity

• IgM or IgG (subclasses IgG1, IgG2, IgG3) bind to cell-surface antigens
• These antibodies fix complement via the classical pathway (starting at C1)
• This triggers the complement cascade, forming the membrane attack complex (MAC) → direct cell lysis
• Alternatively, complement fragments (C3b, C4b) act as opsonins, enhancing phagocytosis

2. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

• IgG antibodies coat the target cell
• NK cells, macrophages, and neutrophils recognize the Fc portion of IgG via Fc receptors (FcγRIII / CD16)
• Effector cells release cytotoxic granules (perforin, granzymes) → target cell death without complement

3. Antibody-Mediated Functional Alteration (Non-cytotoxic subtype)

• Antibodies bind to receptors or functional molecules on cell surfaces
• This can either stimulate or block receptor function without causing cell destruction
• Example: TSH receptor stimulation (Graves' disease) or acetylcholine receptor blockade (Myasthenia gravis)

Key Immunoglobulins Involved

Classic Clinical Examples

Comparison with Other Hypersensitivity Types

Key Distinguishing Features to Remember

• "Self vs. non-self on cells" — the antibody attacks something ON a cell surface or in the extracellular matrix
• Complement fixation is central to most (but not all) type 2 reactions
• The functional subtype (Graves', Myasthenia gravis) does not destroy cells but alters their function — sometimes classified separately as type 2b or receptor-mediated hypersensitivity
• Direct Coombs test is positive in type 2 hemolytic reactions (detects antibody/complement on RBCs)

Core Concept

Subtype 1 — Opsonization and Phagocytosis

Mechanism

• Antibody (IgM or IgG) binds to an antigen on a cell surface (e.g., a red blood cell)
• This triggers complement activation, producing C3b
• C3b coats the cell (opsonization)
• Phagocytes (macrophages) have C3b receptors and Fc receptors → they recognize the coated cell and engulf and destroy it (phagocytosis)

Key Notes from the image

• IgM always comes with C3 (IgM is very efficient at fixing complement)
• The macrophage can eat a whole RBC but NOT a whole glomerular membrane → instead it degranulates and activates complement at that site
• In the spleen, the effector cell is the littoral cell (a specialized macrophage) → it binds to the antibody-coated cell and performs phagocytosis
• Antibodies against cells → go to spleen → littoral cells handle destruction

Clinical Examples

Subtype 2 — Complement-Mediated Inflammation

Mechanism

• Antibody binds to antigen on a cell or tissue surface
• Complement is activated → produces inflammatory fragments
• WBCs are recruited → they degranulate → attract more WBCs → membrane destruction and inflammation
• This is complement OR antibody-mediated inflammation of the cell/tissue, NOT necessarily phagocytosis

Pemphigus Vulgaris Example (from handwritten notes)

1. Ab binds to Ag on skin surface (desmoglein)
2. Activates complement
3. Inflammation → desmosomes separated (skin not intact)
4. Edema forms between layers → bullae/blisters

• The antigen is indirectly destroyed via bystander inflammatory damage

Clinical Examples

Subtype 3 — Antibody-Mediated Cellular Dysfunction

Mechanism

• The cell is not destroyed — its function is altered
• The antibody binds to a receptor on the cell surface
• This can either:
  • Block the receptor → reduced function
  • Stimulate the receptor → excessive function

Clinical Examples

Summary Table — 3 Subtypes at a Glance

Personal Note (bottom right of image)

"Type 2 hypersensitivity is because of antibody's action in 3 ways — mechanism for destruction of a cell..."